As commonly known, controlled release of active substance(s) allows to simplify the patient's administration scheme by reducing the amount of recommended daily intakes, improves patient's compliance, attenuates adverse events, e.g. related to high plasma peaks and improves the bioavailability of the active substance(s). Pharmaceutical controlled release preparations regulate the release of the incorporated active substance(s) over time and comprise formulations e.g. with a prolonged, a sustained, a delayed, a slow or an extended release, so they accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as solutions or promptly dissolving immediate release dosage forms.
There exists always a need to improve the known release systems in order to improve the effectivity of the contained active substances.
Many oral controlled release dosage forms are designed to deliver the doses of a drug at a regulated rate so as to achieve zero-order release kinetics. Irrespective of the type of dosage form, drug solubility and hence absorption depends to a large extent upon the constant changing environmental conditions within the gastrointestinal tract. Many drugs are weak acids or weak bases, or the salts thereof. Therefore, the pH value plays a significant role in the dissolution rate of weakly acidic or weakly basic compounds. It follows therefore that an oral release solid dosage form e.g. containing a weakly basic drug may potentially lead to bioavailability problems. As the drug enters the small intestine, the pH rises to pH 5.5 or higher. In this environment the solubility of a weakly basic drug often decreases greatly and this might translate to a markedly decreased release and absorption in vivo. Therefore, it exists a need to overcome said deficiencies.
In prior art a number of approaches is described which provides a controlled release system. A variety of patent applications relate to pharmaceutical compositions which focus on the fact that the active substance is contained in the core:
For example EP 0 436 370 A1 and U.S. Pat. No. 5,395,628 describe a controlled release pharmaceutical preparation comprising (a) a core containing a pharmaceutically active substance and an organic acid, and (b) a coating film formed on the surface of the core by aqueous coating of a water-insoluble and slightly water-permeable acrylic polymer containing a trimethylammonium-ethyl group.
Furthermore, WO 00/19984 and U.S. Pat. No. 6,878,387 B1 relate to a pharmaceutical preparation consisting of (a) a core containing an active substance, optionally an excipient and common pharmaceutical additives in addition to the salt of an inorganic acid whose proportion in the weight of the core ranges from 2.5 to 97% by weight and (b) an outer film coating consisting of one or more (meth)acrylate copolymers and optionally common pharmaceutical adjuvants, wherein 40 to 100% by weight of the (meth)acrylate copolymers consist of 93 to 98% by weight of radically polymerized C1- to C4-alkylesters of acrylic or methacrylic acid and 7 to 2% by weight of (meth)acrylate monomers with a quaternary ammonium group in the alkyl radical. Preferably the polymers are selected from Eudragit® RS or Eudragit® RL.
However, the systems containing the active substance in the core have disadvantages because the effectivity is not always reliable and the control of dissolving and release of the active substance is not in each and every case sufficient satisfying. Additionally, numerous active substances display a more or less marked tendency to hydrolytic decomposition in the presence of acids and traces of water. In individual cases there may even be a direct chemical reaction between the active substance and organic acids, e.g. ester formation. Therefore, the pharmaceutical preparation does not remain stable when stored.
Furthermore, in prior art controlled release pellets as shown in FIG. 1. are known wherein anions of salts in the core (1) thereof interact via an intermediate layer (2) (modulating layer) with cationic groups of polymers in the outmost coating layer (4) (controlled release layer). Such a composition is described to influence the release of coated pharmaceutical forms during in vitro release. The modulating layer (2) is a neutral polymer layer such as Eudragit® NE. The modulating layer (2) is layered with a drug layer (3) and further coated with controlled release methacrylate polymer having quaternary ammonium ions such as Eudragit® RL/Eudragit® RS as outmost layer (4). According to the supposed release mechanism the ions of core (1) interact with the controlled release layer (4) leading to alterations in hydration of the outmost layer (4) which causes a change in the permeability of said outest layer (4). In other words using the properties of the ion exchanger Eudragit® RS or RL in the outmost layer (4) allows for the change of the permeability of said outest layer in order to control the solubility of the drug. Such controlled release pellets are commercially available under the trademark EUDRAMODE™ by Degussa, Pharma Polymers, Darmstadt.
However, the above controlled release pellets are only tested in vitro and the mechanism based on the above-described ionic interactions resulting in a change of the permeability of the outest layer is very complicated and does not allow a reliable control of the release system. Further the effectivity of an in vivo system is not clarified.
Finally, US 2005/0095293 A1 relates to a pharmaceutical composition with a bioavailability of an active substance which is substantially independent of the gastric pH, for oral administration of active substances with pH-dependent solubilities and a dose number of more than 1 at a pH>5, comprising a plurality of pellets synthesised in each case from a) a core material, b) an optional insulating layer, c) an active substance layer and d) an optional coating, wherein the core material consists of one or more pharmaceutically acceptable organic acid(s) with a water solubility of more than 1 g/250 ml at 20° C., optionally with the addition of binders or other technological adjuvants.
However, the release characteristics of said system of prior art are not always satisfying.
It is therefore an object of the present invention to provide an improved controlled release pharmaceutical system which avoids the disadvantages of the prior art and which allows for a reliable control of the dissolution and release of the pharmaceutically active substance. Furthermore, it shall be possible to adjust a release profile of the active substance which is virtually independent from the pH values of the environmental medium. Furthermore a method of manufacturing the system shall be provided.